This application is a 371 of PCT/JP99/05854, with an international filing date of Oct. 22, 1999, and claims priority of JP 10-320014, filed Oct. 23, 1998.
The present invention relates to novel prostaglandin I2 (abbreviated to xe2x80x9cPGI2xe2x80x9d hereinafter) derivatives and application of the derivatives. Particularly, the present invention relates to novel 5,6,7-trinor-4,8-inter-m-phenylene PGI2 derivatives useful for medicines, and medical application thereof.
PGI2 (prostacyclin) is a compound found by J. R. Vane et al in 1976, which is a substance biosynthesized in the arterial wall from arachidonic acid through endoperoxide (PGH2 or PGG2) and which has a strong platelet aggregation inhibiting effect, gastric acid secretion inhibiting effect, and dilation of the peripheral vascular system. However, PGI2 which has an unstable exo-enol structure is extremely unstable even in neutral aqueous solution and is subjected to conversion to 6-oxo PGF1xcex1 which has little physiological effect. The unstableness of PGI2 causes a great fault in an attempt to use this compound for medicines. PGI2 is also unstable in vivo, and has the fault that the physiological effects are nonpersistent.
On the other hand, the inventors have achieved a series of inventions relating to stable PGI2 derivatives having a skeleton in which the structure of an exo-enol ether moiety which causes the unstableness of PGI2, is changed to inter-m-phenylene (refer to Ohno et at., Japanese Examined Patent Publication Nos. 59-31510, 1-53672, 2-12226, 2-57548, 3-69909, 6-62599, and 7-5582).
Prostaglandin derivatives are used as therapy of ulcers or the like in the digestive area because they are defensive factor potentiators for increasing mucosal blood flow and mucous secretion. However, it is unknown that the PGI2 derivatives have an antibacterial effect on Helicobacter bacteria such as Helicobacter pylori, which attract attention as a pathogenic factor of upper gastric diseases such as chronic gastritis, gastroduodenal ulcer, gastric cancer, lymphoma, etc.
Diseases exhibiting a bleeding tendency due to platelet hypofunction in spite of the normal platelet count are generically named platelet functional disorders. The platelet functional disorders are divided into congenital disorders and acquired disorders. The congenital platelet functional disorders are divided into disorders of platelet adhesion, aggregation and releasing dysfunction.
On the other hand, the acquired platelet functional disorders occur with greater frequency than the congenital disorders, and, for example, the acquired disorders are accompanied with various diseases such as chronic renal failure, liver diseases, blood diseases, and the like, and are caused by extracorporeal circulation or medicines. Furthermore, administration of such medicines for diseases exhibiting the bleeding tendency is dangerous because the bleeding tendency is prolonged. Therefore, it is necessary to prevent the bleeding tendency caused by these diseases and the use of medicines.
Although DDAVP (1-deamino-8-arginine vasopressin) or the like is used for the congenital disorders of platelet releasing dysfunction and the acquired platelet functional disorders, in some cases, arterial thrombosis or hyponatremia occurs as a side effect. Although, in case of emergency, platelet transfusion is conducted, a serious side effect occurs due to the production of antibodies against platelets and lymphocytes.
On the other hand, the inventors have reported that PGI2 derivatives have the effect to potentiate the platelet function without through thromboxane A2 (abbreviated to xe2x80x9cTXA2xe2x80x9d hereinafter) receptors (Miyamdto et al., WO98/11899).
Also the prostaglandin derivatives are known to be useful as medicines for accelerating cervical ripening in the gynecological area.
During pregnancy, the cervical canal is strongly closed for pregnancy continuation up to late pregnancy, for preventing abortion and premature delivery. on the other hand, at the 36th week or later in pregnancy, softening of the cervical canal proceeds for facilitating fetus expulsion, accompanied by dilation of the cervical opening and shortening of the cervical canal length (effacement). This is a phenomenon referred to as xe2x80x9ccervical ripeningxe2x80x9d. The cervical ripening is an important factor which controls the process of fatal delivery. Therefore, in order to safely and normally extract a fetus, it is necessary to sufficiently ripen the cervical canal as a preparatory step for delivery before the start of contraction (pains) of the myometrium.
As a medicine for accelerating ripening of the cervical canal, i.e., a cervical ripening agent, prostaglandin E2 (abbreviated to xe2x80x9cPGE2xe2x80x9d hereinafter) is clinically used. However, PGE2 also has an oxytocic action, and thus has the problem of the possibility of causing excessively contraction of the myometrium. On the other hand, the inventors have reported that PGI2 derivatives are useful as cervical ripening agents without causing the oxytocic action (Ochi et al., WO99/13881).
However, conventional PGI2 derivatives cannot be said to sufficiently remove side effects such as reduction of the blood pressure, etc., and thus the invention of a new PGI2 derivative is in demand.
An object of the present invention is to provide novel PGI2 derivatives having excellent stability in vivo, a strong medical effect, and a little side effect, and medicines each comprising any of the PGI2 derivatives as an active ingredient.
As a result of intensive research, the inventors succeeded in obtaining novel PGI2 derivatives, and found that these PGI2 derivatives have an excellent anti Helicobacter action, platelet function potentiating effect or cervical ripening effect, and the little action to reduce blood pressure as a side effect, resulting in the achievement of the present invention.
Namely, the present invention provides 5,6,7-trinor-4,8-inter-m-phenylene PGI2 derivatives represented by the following formula (I): 
[wherein R1 represents the following: 
wherein R2 is hydrogen, straight chain alkyl having 1 to 4 carbon atoms, branched alkyl having 3 or 4 carbon atoms, trifluoromethyl, xe2x80x94C(xe2x95x90O)xe2x80x94R4 or xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94R4 wherein R4 is straight chain alkyl having 1 to 12 carbon atoms, branched alkyl having 3 to 14 carbon atoms, cycloalkyl having 3 to 12 carbon atoms, aralkyl having 7 to 12 carbon atoms, phenyl, or substituted phenyl (wherein a substituent is at least one of fluorine, chlorine, bromine, iodine, trifluoromethyl, alkyl having 1 to 4 carbon atoms, nitro, cyano, methoxy, phenyl, phenoxy, p-acetamidebenzamide, xe2x80x94CHxe2x95x90Nxe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NH2, xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94Ph, xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94CH3, or xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NH2), two R2 groups may be the same or different, and R3 is hydrogen, alkyl having 1 to 4 carbon atoms, acyl having 1 to 4 carbon atoms, aroyl having 7 to 16 carbon atoms, aralkyl having 7 to 16 carbon atoms, tetrahydropyranyl, tetrahydrofuranyl, 1-ethoxyethyl, allyl, tert-butyl, or tert-butyldimethylsilyl;
(B) xe2x80x94COOR5 
xe2x80x83wherein R5 is:
1) hydrogen or a pharmacologically acceptable cation;
2) straight chain alkyl having 1 to 12 carbon atoms, or branched alkyl having 3 to 14 carbon atoms;
3) xe2x80x94Zxe2x80x94R6 
wherein Z is a valence bond or straight chain or branched alkylene represented by CtH2t wherein t represents an integer of 1 to 6, and R6 is cycloalkyl having 3 to 12 carbon atoms or substituted cycloalkyl having 3 to 12 carbon atoms substituted by 1 to 3 R7, R7 is hydrogen or alkyl having 1 to 4 carbon atoms;
4) xe2x80x94(CH2CH2O)nCH3 
wherein n is an integer of 1 to 5;
5) xe2x80x94Zxe2x80x94Ar1 
wherein Z is defined as the same as the above, and Ar1 is phenyl, xcex1-naphthyl, xcex2-naphthyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, xcex1-furyl, xcex2-furyl, xcex1-thienyl, xcex2-thienyl or substituted phenyl (wherein a substituent is the same as the substituent defined for the substituted phenyl);
6) xe2x80x94CtH2tCOOR7 
wherein t and R7 are defined as the same as the above;
7) xe2x80x94CtH2tN(R7)2 
wherein t and R7 are defined as the same as the above, and two R7 groups may be the same or different;
8) xe2x80x94CH(R8)xe2x80x94C(xe2x95x90O)xe2x80x94R9 
wherein R8 is hydrogen or benzoyl, and R9 is phenyl, p-bromophenyl, p-chlorophenyl, p-biphenyl, p-nitrophenyl, p-benzamidephenyl, or 2-naphthyl;
9) xe2x80x94CnH2nxe2x80x94Wxe2x80x94R10 
wherein W is xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90C(R10)xe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94, and R10 is hydrogen or straight chain or branched alkyl or aralkyl having 1 to 12 carbon atoms, and n is defined as the same as the above; or
10) xe2x80x94CH(CH2OR11)2 
wherein R11 is alkyl or acyl having 1 to 30 carbon atoms; 
wherein R2 is defined as the same as the above, two R2 groups may be the same or different, R12 is hydrogen, straight chain alkyl having 1 to 12 carbon atoms, branched alkyl having 3 to 14 carbon atoms, phenyl, substituted phenyl (wherein a substituent is defined as the same as the substituent defined for the substituted phenyl) or xe2x80x94C(xe2x95x90O)xe2x80x94R4 (wherein R4 is defined as the same as the above);
(D) xe2x80x94CH2xe2x80x94R13 
xe2x80x83wherein R13 is the following: 
wherein R12 is defined as the same as the above; 
wherein X represents xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94; or
(6) azide;
(E) xe2x80x94C(R14)3 
wherein R14 represents hydrogen, fluorine, chlorine, bromine, iodine, cyano or alkyl having 1 to 4 carbon atoms, and all R14 groups may be the same or different; 
wherein R15 represents hydrogen, alkyl having 1 to 4 carbon atoms, phenyl, substituted phenyl (wherein a substituent is the same as the substituent defined for the substituted phenyl), xe2x80x94CH2xe2x80x94OR4 (wherein R4 defined as the same as the above), or a pharmacologically acceptable cation, and two R15 may be the same or different;
(G) xe2x80x94N(R16)2 
wherein R16 is hydrogen, straight chain alkyl having 1 to 12 carbon atoms, branched alkyl having 3 to 14 carbon atoms, cycloalkyl having 3 to 12 carbon atoms, cycloalkylalkylene having 4 to 13 carbon atoms, aralkyl having 7 to 12 carbon atoms, xe2x80x94C(xe2x95x90O)xe2x80x94R4, xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94R4, SO2xe2x80x94R4, phenyl or substituted phenyl (wherein a substituent is defined as the same as the substituent defined for the substituted phenyl), R4 is defined as the same as the above, and two R16 groups may be the same or different (when one R16 represents xe2x80x94SO2xe2x80x94R4, the other R16 is not xe2x80x94SO2xe2x80x94R4);
(H) xe2x80x94(C(xe2x95x90O)CH2)kxe2x80x94H
wherein k represents an integer of 1 or 2; or
(I) xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94CN Y is hydrogen, alkyl having 1 to 4 carbon atoms, fluorine, chlorine, bromine, formyl, methoxy, or nitro, and B is the following: 
xe2x80x83wherein V represents the following:
(1) xe2x80x94CH2CH2xe2x80x94;
(2) xe2x80x94Cxe2x89xa1Cxe2x80x94; or
(3) xe2x80x94CHxe2x95x90C(R7)xe2x80x94;
xe2x80x83wherein R7 is defined as the same as the above, Q is the following:
(1) xe2x95x90O;
(2) xe2x80x94OR3 
xe2x80x94R2 
(3) xe2x80x94R2 
xe2x80x94R2 
R2 and R3 are defined as the same as the above, two R2 groups may be the same or different, R14 is defined as the same as the above, two R14 may be the same or different, and R17 is the following:
(1) xe2x80x94Zxe2x80x94R18 
wherein Z is defined as the same as the above, R18 is straight chain alkyl having 1 to 12 carbon atoms, branched alkyl having 3 to 14 carbon atoms, cycloalkyl having 3 to 12 carbon atoms, cycloalkylalkylene having 4 to 13 carbon atoms, cycloalkyl having 3 to 12 carbon atoms substituted by 1 to 3 R7 (wherein R7 is defined as the same as the above), cycloalkylalkylene having 4 to 13 carbon atoms substituted by 1 to 3 R7 (wherein R7 is defined as the same as the above), phenyl, substituted phenyl (wherein a substituent is the same as the substituent defined for the above substituted phenyl), xcex1-naphthyl, 0-naphthyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, xcex1-furyl, xcex2-furyl, xcex1-thienyl, or xcex2-thienyl;
(2) xe2x80x94Zxe2x80x94Oxe2x80x94R18 
wherein Z and R18 are defined as the same as the above;
(3) xe2x80x94Zxe2x80x94CHxe2x95x90C(R18)2 
wherein Z and R18 are defined as the same as the above, and two R18 may be the same or different; or
(4) xe2x80x94Zxe2x80x94Cxe2x89xa1Cxe2x80x94R18 
wherein Z and R18 are defined as the same as the above; 
wherein Q, R14 and R17 are defined as the same as the above, two R14 groups may be the same or different, and R19 represents fluorine, chlorine, bromine, or iodine; or 
wherein Q, R14 and R17 are defined as the same as the above, two R14 groups may be the same or different, E represents hydrogen or xe2x80x94OR3 wherein R3 is defined as the same as the above, A is the following: 
xe2x80x83wherein m represents an integer of 0 to 5, G represents hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, straight chain alkyl having 1 to 4 carbon atoms, branched alkyl having 3 to 6 carbon atoms, all G groups may be the same or different, and when B of the formula (I) has the structure shown by the definition (A) (except cases where at least one R14 is fluorine, chlorine, bromine, iodine or cyano), and R1 has a structure in which all R2 groups in the definition (A) are hydrogen, or when B of the formula (I) has a structure shown by the definition (A) (except cases where at least one R14 is fluorine, chlorine, bromine, iodine or cyano), and R1 has the structure shown by the definition (B), not all G groups are hydrogen; or 
xe2x80x83wherein j represents an integer of 1 to 4, p represents an integer of 0 or 1, G represents hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, straight chain alkyl having 1 to 4 carbon atoms, or branched alkyl having 3 to 6 carbon atoms, and all G groups may be the same or different; and the formula (I) represents a d-, l- or dl-isomer].
The present invention also provides an anti Helicobacter agent, a platelet function potentiating agent, or cervical ripening agent, which contains any of the above PGI2 derivatives as an active ingredient.
FIG. 1 shows change in mean blood pressure of monkeys after the intravenous administration of compound 5.
FIG. 2 shows change in mean blood pressure of monkeys after the intravenous administration of control compound A.